BibTex format
@article{Torre:2026:10.1161/CIRCRESAHA.125.327497,
author = {Torre, E and Faure, M and Bidaud, I and Baudot, M and Gaillardon, M and Pereira, de Vasconcelos W and Laarioui, S and Talssi, L and Engeland, B and Reiken, S and Saponaro, A and Chen, B-X and Moroni, A and D'Souza, A and Isbrandt, D and Marks, AR and Marx, SO and Mesirca, P and Mangoni, ME},
doi = {10.1161/CIRCRESAHA.125.327497},
journal = {Circ Res},
title = {L-Type Cav1.3 and HCN Channels Mediate Heart Rate Acceleration by Catecholamines.},
url = {http://dx.doi.org/10.1161/CIRCRESAHA.125.327497},
volume = {138},
year = {2026}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - BACKGROUND: The ionic mechanism by which catecholamines increase the heart rate is incompletely understood. In this study, we have assessed the roles of sinoatrial node L-type Cav1.3 (α1D) Ca2+ channels, phosphorylation of L-type channel regulatory partner protein Rad (Ras-related RGK GTP-binding protein), and cAMP-dependent regulation of hyperpolarization-activated HCN (hyperpolarization-activated cyclic nucleotide-gated) channels. METHODS: We studied β-adrenergic regulation of heart rate and sinoatrial pacemaker activity in mice lacking Cav1.3 channels and in mice expressing dihydropyridine-insensitive L-type Cav1.2 channels alone or concomitantly expressing cAMP-insensitive HCN4 subunits in a heart-specific and time-controlled manner. We also studied the chronotropic response to sympathomimetics of sinoatrial pacemaker myocytes under conditions of specific inhibition of cAMP-dependent regulation of HCN4 by the cyclic dinucleotide cyclic di-(3',5')-GMP and ablation of PKA (protein kinase A)-dependent phosphorylation of Rad. RESULTS: Mutant mice with knockout of Cav1.3 and cAMP-insensitive HCN4 subunits in the heart lacked diurnal variation in heart rate and failed to increase their heart rate after administration of catecholamines or during physical activity. Selective pharmacological inhibition of Cav1.3 prevented the enhancement of pacemaker activity by sympathomimetics or by direct activation of adenylate cyclase, as well as by phosphodiesterase inhibitors, when cAMP-dependent regulation of HCN was simultaneously silenced. Upregulation of Cav1.3 and HCN-mediated funny current (If) accounted for the total change in diastolic current on activation of β-adrenoceptors, explaining the loss of chronotropic effect of catecholamines. Preventing PKA phosphorylation of Rad abrogated the chronotropic response to sympathomimetics of intact hearts under HCN blockade, or in pacemaker myocytes on preventing cAMP-dependent regulation of HCN4, respectively. CONC
AU - Torre,E
AU - Faure,M
AU - Bidaud,I
AU - Baudot,M
AU - Gaillardon,M
AU - Pereira,de Vasconcelos W
AU - Laarioui,S
AU - Talssi,L
AU - Engeland,B
AU - Reiken,S
AU - Saponaro,A
AU - Chen,B-X
AU - Moroni,A
AU - D'Souza,A
AU - Isbrandt,D
AU - Marks,AR
AU - Marx,SO
AU - Mesirca,P
AU - Mangoni,ME
DO - 10.1161/CIRCRESAHA.125.327497
PY - 2026///
TI - L-Type Cav1.3 and HCN Channels Mediate Heart Rate Acceleration by Catecholamines.
T2 - Circ Res
UR - http://dx.doi.org/10.1161/CIRCRESAHA.125.327497
UR - https://www.ncbi.nlm.nih.gov/pubmed/41342134
VL - 138
ER -